Nuclear magnetic resonance spectrometer

ABSTRACT

In a nuclear magnetic resonance spectrometer, this invention relates to an improvement of a lock system for stabilizing a magnetic field intensity. It is an object of the present invention to dissolve a low stability by using a conventional voltage control oscillator and a complex operation in the case of varying a reference material for locking. In the present invention, a radio frequency of a high stable reference frequency source is demultiplied by a variable frequency divider so that a frequency modulation or a modulation of the magnetic field is effected by the output thus demultiplied. When the reference material is changed, the operation can easily be made by varying the demultiplication ratio of the variable frequency divider.

TECHNICAL FIELD

This invention relates to a nuclear magnetic resonance spectrometer andspecifically to a nuclear magnetic resonance spectrometer using a locksystem in order to stabilize the magnetic field.

BACKGROUND ART

In a nuclear magnetic resonance spectrometer (hereinafter referredsimply to as "NMR"), stabilization of the magnetic field is essential.Hereinafter the explanation on this necessity will be explained in thecase of NMR for measurement of a hydrogen nucleus (magnetic field=14 KG,frequency=60 MHz). The range of distribution of the NMR signals of thehydrogen nucleus is about 10 ppm. This corresponds to 600 Hz in terms offrequency. On the other hand, the half value width of the resonanceabsorption spectrum is about 0.5 Hz. In order to obtain a stablespectrum, therefore, stability of about 0.1 Hz is necessary between theresonance frequency and the magnetic field. This value is about 10⁻⁹ of60 MHz. The frequency source of NMR in this instance is a crystaloscillator having a stability of about 10⁻⁶ /°C. and stability ofmagnetic force of the magnet is about 10⁻⁴ /°C. Hence, the frequencysource and the magnet are placed inside a thermostatic oven that issubjected to high accuracy temperature control. Further, magneticshielding is applied to them. As a result, it becomes possible to obtainsuch a stability as required for the frequency source against theexternal temperature change or against the disturbance to the magneticfield. Yet, it is not possible to obtain sufficient stability requiredfor the magnet. Hence, the variation of the NMR signal of a specificreference material is fed back as an error signal to the magnet or tothe frequency source. The method of stabilizing the magnetic field usingthis feed-back is called the lock system of NMR. This lock system isdivided into two groups; one being a homonuclear lock system using aspecific NMR signal of a nuclide to be measured and the other being aheteronuclear lock system using an NMR signal of nuclide that isdifferent from the nuclide to be measured.

In the abovementioned NMR for measuring the hydrogen nucleus, problemswith the conventional method will now be explained with reference to theheteronuclear system using a solvent for duterium, by way of example.The resonance frequency of the deuterium nucleus is 9.2 MHz at themagnetic field intensity of 14 KG. Hence, a radio frequency of 9.2 MHzis irradiated onto a sample, which is placed in the magnetic field of 14KG. The solvent for the sample has the deuterium nucleus. On the otherhand, a modulation magnetic field of f KHz is applied to the sample.This frequency f is so set that (9.2 MHz+f KHz) becomes a resonancefrequency of the deuterium nucleus used for locking. The NMR signal ofthe deuterium nucleus is converted into an audio frequency by a phasedetector of 9.2 MHz. Further, the signal of this audio frequency isdetected by a phase detector of f KHz. The output of this detector is anerror signal corresponding to a deviation of the phase of f KHz. Themagnetic field inensity is controlled by feeding back this error signalto a feed-back coil of the magnet.

Now, the distribution range of the NMR signal of the deuterium nucleusin this instance is about 10 ppm (about 90 Hz). Accordingly, theresonance frequency of the deuterium nucleus varies depending on thekind of the solvent for deuterium used for locking. For this reason, anoscillator used for modulating the magnetic field is a voltage controloscillator. The oscillation frequency of this voltage control oscillatoris changed by changing the value of a variable resistor. When the kindof the solvent for deuterium nucleus is changed, therefore, thisvariable resistor is adjusted.

The stability of the voltage control oscillator in this case isextremely low in comparison with that of the crystal oscillator. Hence,the accuracy in stabilizing the magnetic field becomes lower. In recentyear, a method of measurement has been employed which takes an averageof the NMR signals with respect to time in order to improve the signalsensitivity. For this reason, too, requirement for the stability over anextended period is ever-increasing.

In adjusting the variable resistor, calculation of the oscillationfrequency in advance or calibration operation by monitoring the positionof the duterium nucleus signal is necessary.

The abovementioned problems occur not only in the heteronuclear locksystem but also in the homonuclear lock system.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a nuclear magneticresonance spectrometer which enables to stabilize the magnetic fieldwith a high level of accuracy.

It is another object of the present invention to provide a nuclearmagnetic resonance spectrometer having improve performance.

In the present invention, a radio frequency is irradiated onto areference material for locking and is then demultiplied by a variablefrequency divider so that the frequency modulation or the modulation ofthe magnetic field is effected by the output thus demultiplied. Theerror signal arising from the resonance signal of this referencematerial is fed back for the purpose of stabilizing the magnetic field.Since the radio frequency irradiated onto the reference material and themodulation frequency have high stability in this case, it is possible tostabilize the magnetic field with a high level of accuracy. When thereference material for locking is changed, the switching operation ofthe resonance frequency can easily be made by varying thedemultiplication ratio of the variable frequency divider.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram showing an embodiment of the presentinvention; and

FIG. 2 is a circuit diagram of the variable frequency divider of anembodiment of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

An embodiment of the present invention will now be explained byreferring to FIG. 1. Reference numeral 1 denotes a radio frequencyoscillator which generates a signal of 60 MHz and a signal of 9.2 MHz.In other words, a crystal oscillator of 9.2 MHz as the master oscillatoris incorporated in the radio frequency oscillator. The stability of thiscrystal oscillator is 10⁻⁶ /°C. The signal of 9.2 MHz is multiplied by 6times by a frequency multiplier. A signal of 5 MHz is mixed with thesignal of 55 MHz formed by this frequency multiplier, thereby providinga signal of 60 MHz. This 60 MHz signal is applied as input to a pulsemodulator 2. A pulse having a predetermined pulse width is also appliedas input to this pulse modulator 2 from a pulse generator 13.Accordingly, the 60 MHz signal is pulse-modulated in the pulse modulator2 by the pulse generated as output from the pulse generator 13. Thepulse width and the repetition interval of the pulses generated by thepulse generator 13 are controlled by a computor 11. The radio frequencypulse is amplified by a radio frequency power amplifier 3, and isirradiated onto the sample for measurement via a atransmitter coilinside a probe 4. The probe 4 is interposed between a pair of magnets 5and 5'. The magnetic field intensity of the magnets is 14 KG. The freeinduction decay signal (hereinafter referred to as the FID signal)obtained from the sample for measurement by the irradiation of the radiofrequency pulse is detected by a receiver coil inside the probe 4. TheFID signal is amplified by a radio frequency amplifier 6. A gate circuit7 is controlled by the computor 11 in such a manner that it allows thepassage of the signal only in the period except the irradiation periodof the radio frequency pulse. The FID signal passing through the gatecircuit 7 is applied as input to a phase detector 8. The 60 MHz signalfrom the radio frequency oscillator 1 is input to the phase detector 8as the reference signal. Accordingly, the FID signal, that is convertedinto an audio frequency, is generated as output from the detector 8.This FID signal is amplified by an audio frequency amplifier 9 andconverted into a digital signal by means of an analog-digital convertor10. This digital signal is taken into the computor 11. The FID signal,which is once written into the memory of the computor 11 and is atime-axis signal, is subjected to the Fourier transformation and ischanged into a frequency axis signal. This frequency axis signal isrecorded on a recorder 12 as an NMR signal. If necessary, this signal isintegrated several times. The foregoing explanation deals with themeasuring system of the ordinary Fourier transforme type NMR.

Next, the explanation will be given on the lock system. The 9.2 MHzsignal is applied as input to the modulator 14 and to the variablefrequency divider 15 from the radio frequency oscillator 1. The 9.2 MHzsignal applied as input to the variable frequency divider 15 is dividedinto a signal of (5 KHz+g Hz) and the divided signal is in turn appliedas input to the modulator 14. Accordingly, the output signal of themodulator 14 is a signal which is produced when the 9.2 MHz signal ismodulated by the (5 KHz+g Hz) signal. The frequency g Hz in thismodulation frequency can be changed by switching a change-over switch16. The resonance frequency of the duterium nucleus used for locking is(9.2 MHz+5 KHz+g Hz). The output signal of the modulator 14 is amplifiedby a radio frequency power amplifier 17. The amplified signal isirradiated onto the sample for measurement from the transmitter coilinside the probe 4. The solvent for the duterium for locking is usedalso as the solvent for the sample for measurement. The resonance signalobtained from the solvent for the sample for measurement is amplified bya radio frequency amplifier 18. The amplified signal is detected in aphase detector 19 by the 9.2 MHz signal from the radio frequencyoscillator 1. The (5 KHz+g Hz) signal thus detected is applied as inputto a detector 20. After its phase is shifted by 90 degrees by a phaseshifter 21, the (5 KHz+g Hz) signal generated as output from thevariable frequency divider 15 is impressed as input to the detector 20.Accordingly, the dispersion signal is generated as an error signal fromthe detector 20. This error signal is amplified by an error amplifier 22and applied to a feedback coil 23. The feed-back is carried out so thatthe error signal becomes zero thereby to control the magnetic fieldintensity.

Next, the construction of the variable frequency divider 15 will beexplained by referring to FIG. 2. Various solvents are available as thesolvent for duterium. The resonance frequency of chloroform-d (CDCl₃),for example, is 9.212764 MHz at 14,100 KG. In this case, the masteroscillator of the radio frequency oscillator 1 accurately has anoscillation frequency of 9.207760 MHz. Accordingly, it is possible toobtain the resonance frequency of 9.212764 MHz by adjusting the outputof the variable frequency divider 15 to 5.004 KHz. In other words, whenCDCl₃ is used as the solvent, the demultiplication ratio of the variablefrequency divider 15 may be set to 1/1840. In FIG. 2, reference numeral151 designates an invertor and numerals 152, 153 and 154 do 4-bitup-down counters, respectively. These up-down counters use HD 74193, aproduct of Hitachi Ltd. Reference numerals 155 and 156 representoctal-to-binary decoders, respectively. They are HD 74148, a product ofHitachi Ltd. Reference numeral 157 represents a nand circuit. Thedecoders 155, 156 and the nand circuit 157 together form ahexadecimal-to-binary decoder. The inputs I0, I1, . . . I7 of thedecoders 155, 156 are generally at "1" level. When the change-overswitch 16 is changed over to the input I0 of the decoder 155, the inputI0 becomes "0" level. At this time the level of A0, A1 and A2 of thedecoders 155, 156 are "1" while the level of E1 is "0". Hence, theinputs A, B, C and D of the counter 152 become "0" level, respectively.On the other hand, the inputs A, C and D of the counter 153 are set inadvance to "0" level and the input B is set in advance to "1" level.Further, the inputs A, B and C of the counter 154 are set in advance to"1" level and the input D, to "0" level. The demultiplication ratio(1840) of the chloroform-d in this instance is "730" in terms of thehexadecimal notation. In other words, the counters 154, 153 and 152 arerespectively set to "7", "3" and "0" in order named. A pulse isimpressed as input to a count-down terminal CD of the counter 152 fromthe master oscillator of the radio frequency oscillator 1. Since thecounter 152 is set to "0", a pulse is generated as output from a borrowterminal B when 16 pulses are counted. The content of the counter 153 ischanged by this pulse from "3" to "2". Whenever the counter 152 counts16 pulses, a pulse is generated as output from the borrow content B.When the content of the counter 153 becomes "0", a pulse is generatedfrom a borrow terminal of the counter 153. This pulse changes thecontent of the counter 154 from "7" to "6". Whenever the counter 153counts 16 pulses, a pulse is generated from the borrow output. When thecontent of the counter 154 becomes "0", a pulse is generated from theborrow terminal and a QC terminal. This pulse is generated whenever 1840pulses are applied as input to the counter 152. The output pulse of theborrow terminal B is impressed as input to load terminals L of thecounters 152, 153, 154 whereby the contents of the counters are loaded.

The QC output of the counter 154 is inverted by an inverter 158. As theabovementioned actions are repeated, the counter 154 produces one pulsefrom the QC terminal whenever 1840 input pulses are applied to the CDterminal of the counter 152. In other words, the 9.2 MHz radio frequencysignal is demultiplied by the variable frequency divider 15 into the5.004 KHz signal, more accurately into the 5.00422 KHz signal. Thissignal is deviated by 0.22 Hz from the practical resonance signal ofchloroform-d. As a result, the magnetic field intensity is controlled toa value which is deviated by 0.22 Hz from the original value. However,the frequencies used for the purpose of lock are 9.2 MHz of the crystaloscillator as the master oscillator and 5 KHz that is obtained bydividing this 9.2 MHz frequency, and each has stability of 10⁻⁶ /°C.Accordingly, when the measurement is carried out repeatedly, thedeviation of the magnetic field intensity is always constant. Inconjunction with the NMR spectrum as the frequency axis signal, thismeans that the frequency as the axis of abscissa is constantly deviatedby a predetermined quantity. When the NMR spectra are integrated byrepetition of the measurement, broadening of the peak width due tounstability of the axis of abscissa does not occur. In recording the NMRspectra onto a recorder or the like, the deviation of the axis ofabscissa can be compensated for either manually or automatically. Thiscompensation method will later be described.

When the solvent for duterium is changed, change of the lockingfrequency can be made by turning a knob 24 fitted onto the operationpanel of the NMR spectrometer. A label 25 is put below the knob 24 onthe operation panel in order to mark the name of the solvent forduterium used for locking. When the solvent is changed from chloroform-dto duterium oxide D₂ O, for example, the knob is to be turned to theposition of D₂ O on the label 24. In this case, the change-over switch16 sets the input I7 of the decoder 155 to "0" level. The resonancefrequency of duterium oxide is 9.212745 MHz. Hence, the demultiplicationradio of the variable frequency divider 15 is to be set to 1/1847 (to737 in the hexadecimal notation). The resonance frequency ofdimethylsulfoxide-d₆ [(CD₃)₂ SO₄ ] is 9.212723 MHz. Hence, thedemultiplication ratio of the variable frequency divider 15 is to be setto 1/1855 (73F in the hexadecimal notation) in this case. Theabovementioned three kinds of solvents are very often used as thesolvent for duterium.

For solvents for duterium in general including acetone-d₆ [(CD₃)₂ CO]and benzene-d₆ (C₆ D₆) that are put on the label 25, thedemultiplication ratio of the variable frequency divider 15 may be 1/73X(where X is O-F). Accordingly, the values of the counters 153, 154 ofthe variable frequency divider 15 in FIG. 2 are set respectively to "7"and "3". However, when acetic acid-d₄ (CD₃ COOD) or the like is used asthe solvent, it is necessary to change the second digit of thedemultiplication ratio. The circuit configuration in such a case may aswell be that of the input circuit for the counter 152 shown in FIG. 2.

Next, the explanation will be given on the compensation method of thedeviation of the axis of abscissa when the NMR spectra are recorded ontoa recorder or the like. The deviation of the locking frequency is 0.22Hz in the case of chloroform-d and this deviation is about 0.02 ppm interms of the frequency axis of the NMR spectra and is a slightdeviation. The deviation can manually be compensated in the followingmanner. An ordinary NMR spectrometer is equipped with a CRT display.Hence, the NMR spectral signals stored in the memory are displayed onthe CRT. Thereafter the luminous point is displayed on the CRT. Anoptional peak is selected from the NMR spectra displayed on the CRT. Theexample of the peak to be selected is tetramethylsilane (TMS). Theluminous point is moved along the axis of abscissa through theadjustment of the volume till it is in conformity with the peak of TMS.The quantity of movement of the luminous point till it coincides withthat of TMS is written into the computor. The addresses of the memoriesof the computor and the axis of abscissa of the NMR spectra are arrangedin advance so as to correspond to one another. It will therefore beassumed that No. 100 address of the memory corresponds to 0 ppm of theNMR spectrum. The moving quantity of the luminous point to be read intothe computor also corresponds to the displacement of the address. Whenthe moving quantity of the luminous point corresponds to 10 addresses,for example, the computor judges that No. 110 address corresponds to 0ppm of the NMR spectrum. In recording the NMR spectra onto a recorder,the data of the No. 110 address are output at the position of 0 ppm ofthe recording sheet.

Next, the explanation will be given on the automatic compensation methodof the deviation. The deviation of the locking frequency in the systemshown in FIG. 2 is maximum±1.355 Hz. For compensating for the deviationusing the peak of TMS, the data of the addresses in the rangecorresponding to±0.2 ppm, for example, are compared with the address ofthe memory corresponding to 0 ppm of the NMR spectrum in order to detectthe address having the peak data. It is possible to judge theabovementioned peak data as the peak of TMS since there is generally noother peak within the range of±0.2 ppm than the peak of TMS. Inrecording the NMR spectra on the recorder, the data located at theaddress of the abovementioned peak data is generated as output to theposition of 0 ppm on the recording sheet.

The foregoing explanation covers the case where duterium lock is carriedout in a Fourier transforme type NMR spectrometer for the measurement ofhydrogen nucleus having the frequency of 60 MHz and the magnetic fieldintensity of 14 KG. However, the values of the frequency and themagnetic field intensity may be optional and the invention can besimilarly applied to an NMR spectrometer of 90 MHz-21 KG type. Thenuclide to be measured may be a carbon nucleus or a fluorine nucleus inaddition to the hydrogen nucleus. Further, the nuclide used for lockingmay also be fluorine besides duterium. In the Fourier transforme typeNMR spectrometer, it is difficult to employ the homonuclear lockingsystem using a nucleus which is the same as the nucleus to be observed.Hence, the invention is specifically effective for the heteronuclearlocking system. In a NMR spectrometer of the CW system, the presentinvention is effective if the locking frequency can be fixed. Though theresonance frequency of the duterium nucleus used for locking is changedover in the above-described embodiment, the frequency of the measuringsystem may be changed over while the frequency of the locking system isfixed at a predetermined value. In the embodiment described above, thefrequency modulation is carried out by means of the modulator 14.However, modulation of the magnetic field may be carried out by means ofa modulation coil wound onto the magnet. In the detector 20, the errorsignal is obtained as the dispersion signal by carrying out thedetection while the pase is deviated by 90 degrees, but this may be anabsorption signal. Furthermore, the locking system may be an internallock or an external lock.

I claim:
 1. A nuclear magnetic resonance spectrometer comprising: meansfor generating a unidirectional magnetic field; means for placing asample and a reference material in said unidirectional magnetic field;means for generating a radio frequency; means for supplying said radiofrequency to said sample and to said reference material; means fordetecting the resonance signal obtained from said sample and obtaining anuclear magnetic resonance spectrum; a variable frequency dividercapable of optionally dividing the frequency of said radio frequency;means for modulating one of said radio frequency irradiated to saidreference material and said magnetic field in accordance with the outputsignal of said variable frequency divider; means for obtaining an errorsignal from the resonance signal obtained from said reference material;and means for controlling the intensity of said magnetic field on thebasis of said error signal.
 2. The nuclear magnetic resonancespectrometer as defined in claim 1 further including a switchingmechanism for switching the demultiplication ratio of said variablefrequency divider to a predetermined demultiplication ratio.